Project Summary/ Abstract The PBPK model based prediction of the skin absorption and following local and systemic exposure assessment has become a widely accepted scientific tool. One of the benefits from using such tools, conditional to proper verification, is the ability to test virtual scenarios. This applies to situations that are not easily tested in a clinical trials setting, including the exposure assessment in the disease individuals. The current project aims to further enhance the currently available Physiologically Based Absorption and Pharmacokinetic (PBPK) MPML MechDermA skin model with the quantitative description of the disease triggered histological and functional modifications of the skin. This includes, but is not limited to, thicknesses of various skin layers, presence of cracks, dryness, modification of the blood flow and skin temperature, sebaceous glands infection and inflammation, flaking, presence of pustules, comedones, vacuoles, cysts, and pseudocysts. All the above listed parameters, and others if necessary, will be collected and annotated in the database. The planned flexible database will eventually support full parametrization of the MPML MechDermA skin model towards various diseases of users? choice. Thus, such structure will eventually allow for infinite upgrades towards both histopathological and morphological modifications and diseases with clinical manifestation in skin and subcutis layers. The innovation lies in the planned research strategy, and flexibility of the proposed approach. The histopathological modifications of the healthy skin will be used as the building blocks allowing for ad hoc development of the disease of interest. Apart from the database, the set of the pre-defined combinations of parameters for the most important diseases, from the drug absorption point of view, will be provided (including, but not limited to Acne, Psoriasis, Sunburn, Rosacea, Dandruff, Actinic Keratosis and Atopic Dermatitis). The database will be fully ? functionally and conceptually ? connected with the Simcyp Population-Based ADME Simulator, thus allowing for the clinical trials simulation incorporating inter- and intra-individual variability assessment. An important element of the project will be a quantitative verification of the developed database together with the pre-defined diseases (sets of connected building blocks) versus the literature derived clinical reports data. Part of this element includes dissemination of the project findings via webinars, conference presentations, and full text publications.